New Understanding of Genes May Lead To New Scleroderma Treatment

New Understanding of Genes May Lead To New Scleroderma Treatment

New insights into the workings of genes are bringing hope for a revolution in scleroderma research and scleroderma treatment. Scleroderma (also called systemic sclerosis) stiffens connective tissue and decreases blood vessel formation throughout the body, scarring the skin and triggering potentially lethal damage to vital organs.

While rheumatic diseases often run in families, scleroderma does not result from a faulty gene. Instead, scientists suspect that the disease results from subtle flaws in how our cells read the genes. Researchers theorize that such “epigenetic” changes disrupt gene expression without altering the DNA sequence.

With funding from the Arthritis National Research Foundation, Eliza PS Tsou, PhD who is the Edward T. and Ellen K. Dryer Early Career Professor of Rheumatology at the University of Michigan, is investigating how epigenetics influences both skin thickening and impaired blood vessel formation in scleroderma.

“New understanding of gene expression may completely change how we treat scleroderma,” says Dr. Tsou. “The high mortality rate and few therapeutic options reflect our lack of understanding of the underlying molecular mechanisms in scleroderma. Our goal is to understand the disease and identify targets for scleroderma treatment and a potential cure.”

How can researchers identify environmental or external triggers that cause scleroderma to erupt in susceptible individuals? What switches the genes off and on?

Like other inflammatory disorders, there is no cure for scleroderma, or even an accepted disease-modifying scleroderma treatment. The chronic autoimmune disease causes the body to attack the joints, skin and internal organs—lungs, heart, GI tract and kidneys—often with life-threatening consequences. So far, researchers have had no luck developing pharmaceuticals for the devastating disorder because the cause of the disease remains so elusive.

“What makes my project unique is that I am able to isolate two cell types from patient skin biopsies,” says Dr. Tsou. “Some cells are from the blood vessels while others cause the skin to thicken. From these cells we can examine directly why they are sick, why they behave differently from healthy cells, and identify the pathways or molecules that are causing them to act abnormally. Once these targets and pathways are identified, we can work on ways to intervene and see if our strategy would work to make these sick cells normal again.”

Dr. Tsou is tackling the key epigenetic players that stiffen skin and hinder blood vessel formation. Her lab is one of the few in the world that can isolate and grow these blood vessel cells for research.

“Although the skin thickening cells are easy to isolate, the blood vessel cells are more difficult to purify,” says Dr. Tsou, whose research showed that a substance called HDAC5 blocks blood vessel formation in scleroderma. “When we decreased the expression of HDAC5 in scleroderma cells, those cells resumed their normal function.”

Using next-generation techniques to scan the genes in blood vessel cells and supercomputers to crunch the data, she discovered a protein called CYR61 that is crucial for scleroderma blood vessel cell function and also slows skin thickening. With her Arthritis National Research Foundation grant, she is expanding on her previous research.

“We hypothesize that CYR61 is beneficial for scleroderma through its anti-skin thickening and pro-blood vessel growth properties,” says Dr. Tsou, who is fascinated by the possibilities of potential drug development. “Since CYR61 can tackle the blood vessel and skin thickening problems at the same time, it will be a great candidate for drug target. We are testing this hypothesis and so far we are very hopeful for the future.”

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Arthritis National Research Foundation

derek@curearthritis.org

The Arthritis National Research Foundation's mission is to provide initial research funding to brilliant, investigative scientists with new ideas to cure arthritis and related autoimmune diseases. Writing articles about the patients affected and the science being done to find a cure shows why we need to come together to #CureArthritis!